Thomas f



Patented Oct. 24, 1950 1 UNITED STATES PATENT OFFICE -,B-NITROALKYL BARBITURIC ACIDS AND SALTS THEREOF Carl T. Bahner, Jefferson City, Tenn.

No Drawing. Application August 5, 1948, Serial No. 42,741

hypnotic, sedative or soporific activity, and as intermediates in the preparation of other pharmaceuticalsand chemical compounds. 7

The compounds that are contemplated within the scope of this invention are those which have the following skeletal configuration:

It will be noted from (1) that the ring nucleus is of the barbituric acid type and is that which is found in such compounds as barbituric acid, 2- th-iobarbituric acid and malonylguanidine. As is well known in the art, the acid characteristics oflcompounds having this skeletal arrangement are imparted by the hydrogen; atoms attached to the nitrogens in the 1 and/or 3 positions, and the salts of the compounds having the above indicated skeletal configuration are to be considered as falling within the scope of this invention as defined by the appended claims. Stated in another way, this invention relates to the provision of compounds having a barbituric acid type ring nucleus wherein is provided a 2'-nitroalkyl substituent on the carbon atom in the 5 position.

More specifically, this invention relates to compounds (and their salts) having the formula:

Norm" o H Rat -5H MI wherein R1 is selected from the group consisting of hydrogen and alkyl, wherein R2 is selected within the above generalized formula and contemplated within the scope-of this invention are 5-(2nitrol-ethyl-n-butyl) barbituric acid, 5- (2 -nitro-l' phenylethyl)-barbituric acid, 5-12.- nitro-n-butyl) -2-thiobarbituric acid, 5-(2-nitron-butyD-barbituric acid, 5-(2-nitro-l-phenylethyl) -2-thiobarbituric acid, 5-ethy1-5-(2-nitron-butyD- barbituric acid, 5-methyl-5-(2'-nitro n-butyl) 2 thiobarbituric acid, 5 allyl-5-(2'- 'nitio-n-butyl) -barbituric acid, 5 benzyl-5-(2'- niti'o-n-butyl) barbituric acid, and the salts thereof. Specific salts that may be mentioned are those of potassium, barium,: calcium and those formed from a quaternary ammonium hydroxide, such as benzyltrimethylammoniumv hydroxide or tetraethanolammonium hydroxide.

' These latter salts are important as intermediates formed When one phase of this invention is carried out in accordance with a preferred embodiment, as will be hereinafter mor fully explained.

As above indicated, the compounds of this invention are barbituric acid derivatives butit will be apparent that the oxygen onthecarbon atom in the 2 position of the barbituric acid nucleus may be replaced by sulfur to form the corresponding Z-thiobarbituric acid derivative or its salts, or by an imido group to form the corresponding de rivative of malonylguanidine or its salts.

The compounds of this invention may be prepared by reacting a nitroolefin directly with a salt of the barbituric acid type compound whereby the nitroolefin is added to the barbituric acid type nucleus at the carbon atom in the 5 position. The over-all reaction may be represented as 1'01- 1OWS:

l ino;

O C=X (salt) 40 (1311 Rs CN NOrRr- O H" na l am ,l r C=X (salt) The salts of; fl cpbarbituric acid type compounds which have been foundto be particularly ffective for carrying out the reaction are those of potassium and of benzyltrimethylammonium V hydroxide. However, in most instances, other salts may readily be used, such as those of sodium,

lithium, calcium, magnesium, barium, tetra- 3 ethanolaminonium hydroxide and the like, the desirability being that such salts be soluble in the solution in which the reaction is efiected.

It will be apparent that the above indicated generalized equation indicates that a convenient method has been devised in accordance with this invention for adding a finitroalkyl group to a compound of the barbituric acid type wherein the carbon atom in the 5 position has attached at least one unsubstituted hydrogen atom. The metallic salts of the barbituric acid type compound are very satisfactory for use in the cases where neither hydrogen on the 5 carbon atom is substituted. However, in those cases where one of the hydrogens on the 5 carbon atom has already been substituted, such as by an alkyl or an aryl group, then it is preferred to employa quaternary ammonium salt of such a 5 monosubstituted barbituric acid derivative in the reaction with the nitroolefin. When a quaternary ammonium salt is employed (for example, a benzyltrimethylammonium salt), the addition of the nitroolefin to the carbon atom in the 5 position will readily occur even though one of the hydrogens on the 5 carbon atom has been previously substituted with another grouping, such as methyl, ethyl, n-butyl or benzyl. Thus by the use of the quaternary ammonium salts, a method has been devised for the ready preparation of 5-alkyl-5- (2'-nitroalkyl) -barbituric acid type compounds directly from the corresponding 5-alkyl compounds. :Such a process and the resulting product constitute onefeature of the present invention.

In accordance with a further and alternative embodiment of this invention where it is desired to provide an alkyl substituent on the carbon atom in the 5 position together with the fi-nitroalkyl substituent, it has been found that this may be accomplished by the direct alkylation of a 5- (2',-nitroall yl) -barbituric acid type compound with an alkyl halide. Thus an alkyl group is added to the nucleus at the carbon atom in the 5 position. The alkylation reaction is preferably carried out with the salt of the 5-(2-nitroalkyl) barbituric acid type compound, and the over-all reaction may be represented as follows:

The alkyl or aralkyl halides employed in this alkylation reaction maybe any that are Well known in the art to 'beuse'fulforalkylation of readily alkylatedcompounds such as malonic ester. Generally thehalide should be a chloride, bromide or iodide, suitable examples being methyl iodide, allyl bromide and benzyl chloride. Other halides, such as ethyl, propyl, n-butyl, iso-butyl,

benzyl, etc. may be used.

In carrying out the addition ofa nitroolefin to a'salt of barbituric acid type compound as indicated'in the foregoing, the salt employed is prefrably one which is readily ionized in solution and is readily soluble in the solvent employed.

4 The potassium salts are convenient but the presess is not limited to them, since, as above explained, under special conditions, the quaternary ammonium salts, such as the benzyltrimethylammonium salt, are preferred. If desired, a trace of acid may be used in the reaction mixture to inhibit the polymerization of the nitroolefin. The reaction is effected most conveniently in a solution which serves as a solvent for both the salt and the nitroolefin and does not react with or destroy either. For example, mixtures of alcohols and water have been found useful but the process is not to be considered as limited to these particular solvents. Generally speaking, when the metallic salts are employed, it is desirable to carry out the nitroolefin addition reaction at elevated temperatures since the reactants are usually more soluble in hot solvents and since elevated temperatures have a tendency to speed up the reaction. However, lower temperatures are preferred when the quaternary ammonium salts are utilized. After the addition reaction has taken place, the resulting 5-(2'-nitroalkyl) derivative may be isolated in the form of its salt by any convenient method. Often the salt form is most convenient for medicinal use or for usein preparing other compounds. If desired, salts containing other cations-may be prepared by metathesis or the corresponding free barbituric acid type derivative may be obtained by cautious acidification of the salt formed in the reaction. As previously indicated, both the salts and the free acids are considered as falling Within the spirit and scope of this invention. 7

For a more complete understanding of this invention, reference will now be made to certain specific examples wherein are indicated certain of the new compounds herein contemplated together with their method of preparation. It will be understood, however, that this invention is not to be restricted in any way by these specific examples since they are merely illustrative and not definitive of the broad aspects of the present invention.

EXAMPLE I 5- (2-m'tro-1 '-ethyl-n-butyl) -barbituric acid v A mixture of 0.78 gram of 3-nitro-3-hexene, 1.0 gram of potassium barbiturate containing a trace of free barbituric acid, 5 cc. of ethyl alcohol and 2 cc. of water was refluxed for 3 hours. The nitroolefin and the barbiturate reacted to form potassium 5-(2'-nitro 1-ethyl-n-butyl)- barbiturate. This salt was recovered by coolmg the reacted solution to room temperature and adding 5 cc. of acetone to precipitate unreacted pbtas'siurn barbiturate. The solution was filtered and the filtrate was evaporated to dryness. The residue was washed with acetone. The washed d'ried'p'owde'r was analyzed for posassium. Calculated for potassium 5-'(2-nitro-'1-ethyl-nbutyl)-barbiturate: 13.3%; found, K, 13.4%,

The freeacid may be prepared from the salt by cautious treatment with an acid, such as monochloracetic acid or dilute sulfuric acid.

EXAMPLE II M 5-;(2' ni tro- 1'-phenyletliyl) -barbitmzc dam A mixture of 2.69 grams of w-nitros'tyrene, 3.00 grains'of'potassium barbiturate, 5.4 cc, of water and 15 cc. 'of ethyl alcohol was refluxed for 1'7 hours and then diluted with 15 cc. of acetone. The precipitate obtained on cooling to room temperature and filtering weighed 0.708- gram and contained some unreacted potassium barbiturate. The filtrate on evaporation yielded 323 grams of crude potassium '5- (2-nitro-1-phenylethyl) barbiturate from which the purified salt was obtained by recrystallization from absolute ethyl alcohol. The free acid was liberated by treatment of an aqueous solution of the potassium salt with a solution of monochloracetic acid.

EXAMPLE III (2 '-11,z'tro-n-butyl) -2-thiobarbituric acid A saturated solution of potassium Z-thiobarbiturate was prepared by boiling a mixture of 275 cc. of 95% ethyl alcohol and 140 cc. of water with 9.4 grams of the potassium salt. The hot solution was decanted and to it was added 6.0 grams (an excess) of 2-nitro-l-butene. The remainder of the undissolved salt was dissolved in 125 cc. of boiling Water and added to the'reaction mixture. The solution was allowed to cool and within a short time the lachrymatory odor of nitroolefin had disappeared. On evaporation of the solution to drynessa nearlytheoretical yield of crude potassium 5-(2-nitro-n-butyl)-2-thiobarbiturate was obtained. Impurities were removed by dissolving a 3.0 g. portion of the crude salt'in 25 ml. of boiling absolute methyl alcohol, allowing to stand with 0.2 g. activated charcoal at 65 C., fitering, adding 40 ml. of dry ether-to the filtrate, cooling, filtering again to remove dark-colored impurities, then evaporating the filtrate to obtain the purified salt.

Analysis: Calculated for potassium 5-(2-nitro n-butyl) -2-thiobarbiturate: K, 13.79%; found, K, 13.56%, 13.53%. i

The corresponding barium and calcium salts were separately prepared by adding concentrated solutions of barium chloride and calcium nitrate, respectively, to separate concentrated clarified solutions of the potassium salt. The barium and calcium salts, respectively, precipitated out. These alkaline earth metal salts were much less soluble in water than was the potassium salt, but were nevertheless somewhat soluble.

The free 5-(2-nitro-n-butyl) -2-thiobarbituric acid was prepared (1) by the cautious addition of a very dilute solution of sulfuric acid to an aqueous solution of the barium salt, and (2) by a similar addition of a solution of a solution of the calcium salt.

5- (z'mitro-n-butyl') -barbitm'ic acid oxalic acid to tion yielded 18.6 grams of crude potassium 5- (2-'nitro-n-butyl-) -ba .rbiturate. In order to obtain the free acid, 7.0 grams of this crude'saltwere dissolved in 20 cc. of water and thesolution. was acidified by the addition of a solution of 2.0 grams ofconcentrated sulfuric acid-in 20 cc. of water over a period of 30 minutes; keeping the solution cooled and wel-listirred. During this period the weight of free acid which separated in the form of white crystals was 2.7 grams. An additional quantity of the free acid was recovered by extracting the aqueous mother liquor with ethyl ether. After recrystallization, the acid small amount of solid matter.

.melted at C. Analysis: Calculated for5- (2'-nitro-n-butyl) -barbituric acid: C, 41.92%, H, 4.33%; found: C, 41.97%, H, 4.91%.

In the foregoing examples an embodiment of this invention has been illustrated wherein the potassium salts of barbituric acid were employed. As previously indicated, and in accordance with one preferred embodiment of this invention, it has been found under certain conditions advantageous to use a quaternary ammonium salt of the barbituric acid type compound instead of the alkali metal salt. When such quaternary ammonium salts are employed, the reaction may then be carried out in more concentrated solutions and at lower temperatures. Likewise the use of these salts is particularly desirable when it is desired to react a nitroolefin with a barbituric acid type derivative which already has one alkyl or aryl substituent on the carbon atom in the 5 position since very much improved yields are obtained (see particularly Example VIII). The next four examples are illustrative of processes in which a quaternary ammonium salt of the barbituric acid type compound is employed in reactions involving nitroolefins.

EXAMPLEV 5-(2'-m'tro-n-butyl)-bdrbituric acid 7 tion which is sold and distributed by Rohm &'

Haas Co., of Philadelphia, Pa.). To this solution was added 5.06 grams of -nitro-1-butene in small portions with stirring, employing a water bath to prevent the temperature from rising above about 40 C. The odor of the nitroolefin-was no longer observed after a short period.

After the solution had been allowed to stand for four days (this period of standing not being necessary), it was centrifuged to remove a Thereafter the 5- (2' -nitro-n-butyl) Y barbituric acid benzyltrimethylammonium saltwas treated in the supernatant liquid by the addition of 4.0 grams of concentrated sulfuric acid dissolved in 20 cc. of water. The dilute acid was added dropwise with stirring over a 30 minute period, keeping the solution cooled. The weight of crude product which separated in the form of tan crystals was 13.3

grams. A single recrystallization from isopropyl alcohol was sufficient to yield nearly pure 5-(2- nitro-n-butyl)-barbituric acid melting at, 152 to 154 C.

The benzyltrimethylammonium salt of 2-thiobarbituric acid was prepared by adding to 2.25

grams of Triton B enough 2-thiobarbituric acid (about 0.760 grams) to produce a neutral solu- Ition. After 30 minutes a solution of 0.70 gram of 1-nitro-2-phenylethylene in 2.5 cc. of absolute ethyl alcohol was added. The solution remained clear on standing overnight but upon seeding deposited crystals of the benzyltrimethylammonium salt of 5-( '-nitro-l-phenylethyl) -2-5thiobarbituric acid. The crystals were washed with 5 cc. of ethyl alcohol and were dried. The crystals had a melting point of to 191 C. and 1.45 grams were recovered. The corresponding. free i alcohol and water.

acid was obtained by dissolving 0.80 gram of the salt in 50 cc. of water to form a saturated solution and then adding 1 cc. of 3 N. hydrochloric acid at room temperature. The free acid separated out in the form of white crystals.

EXAMPLE VII (2 -m'tro-1 -phenylethyl) -barbituric acid.

,5-(2 nitro-l phenylethyl)-barbituric acid began to precipitate. This salt was recovered by filtration and washed with a mixture of ethyl It weighed 30 grams and decomposed at 175 C. An additional 0.9 gram of the salt was recovered from the mother liquor.

The free acid was obtained by dissolving 1.0 gram of the salt in 5 cc. water at 60 C. and adding 1 cc. of 3 N. hydrochloric acid dropwise with stirring. The oily droplets of the acid which first separated soon solidifiedin an amount corresponding to 0.62 gram.

EXAMPLE VIII 5 -ethyl-5- (2'-nitro-n-butyl) -barbituric acid The benzyltrimethylammonium salt of 5-ethylbarbituric acid was prepared by dissolving 1.85 grams of 5-ethylbarbituric acid in 4.4 grams of Triton B and 2.5 cc. of 95% ethyl alcohol to form a neutral solution. To this solution 1.17 grams of 2-nitro-1-butene were added dropwise with stirring employing an ice bath to prevent the temperature from rising above 50 C. The lachrymatory odor of the nitroolefin disappeared at once. The following day cc. of water were added to the reaction mixture and it was centrifuged to remove some gummy material which separated. The resulting clear solution of the benzyltrimethylammonium salt of 5-ethyl-5-(2- nitro-n-butyl)-barbituric acid was acidified by the addition of 1.0 gram of concentrated sulfuric acid dissolved in 8 cc. of water dropwise with stirring and cooling over a 10 minute period.

Additional gummy material formed was separated and the clarified solution was allowed to evaporate until crystals formed which were recovered by filtration, washed with water and h monium salts may be employed if desired. For

example,tetraethanolammonium salts have been used. As will be apparent to one skilled in the art, those quaternary ammonium salts that are preferred for use are those which are soluble to a substantial degree in the solvents employed for the nitro'lefin addition reaction.

In order to demonstrate that aspect of this inven ion when r lates to the preparation of? 5- alkyl-5- 2-nitroall yl) barbituric acid type combarbiturate.

pounds by alkylation in accordance with this invention, the following three examples are given:

EXAMPLE IX 5-m'ethyl-5-(2-nitro-n-butyl) -2 thiobarbituric acid A solution was prepared comprising 73 cc. of absolute methyl alcohol, 14.5 cc, of methyl iodide and 7.0 grams of potassium 5-(2-nitro-n-butyl) 2-thiobarbiturate, the latter being prepared in accordance with the method indicated in Example III. The solution was refluxed for 24 hours, then filtered and the filtrate evaporated to dryness. The crude product was purified by dissolving in 24 ml. of hot alcohol, then throwing out of solution by addition of water and cooling. After two further crystallizations from isopropyl alcohol it was obtained in the form of crystals melting at 203 C. with decomposition. Analysis: Calculated for 5-methyl-5-(2-nitro-n-butyl) -2- thiobarbituric acid: C, 41.69, H, 5.05; found: C, 41.85, H, 5.02.

EXAMPLE X 5 -allyZ-5 (-2-m'tro -n-butyl) -barbit'uric acid A solution was prepared containing 105 cc. of ethyl alcohol, 7 .0 grams of allyl bromide and 7.0 grams of potassium 5-(2-nitro-n-butyl) barbiturate, the latter having been prepared in accordance with the method indicated in Example IV above. The resulting solution was refluxed for 24 hours, cooled and filtered to remove byproducts. The filtrate was evaporated to dryness EXAMPLE XI 5-benzyZ-5- (2'-nitro-n-butyl) -barbituric acid A solution was prepared containing 104 cc. of 91% ethyl alcohol, 5.0 grams of benzyl chloride and 4.5 grams of potassium 5-(2-nitro-n-butyl) The solution was refluxed for 24 hours, cooled and filtered to'remove potassium chloride. The filtrate was evaporated to dryness and the residue was recrystallized first from hot absolute alcohol, by addition of water and cooling, then from 95% alcohol to form white crystals which melted with decomposition at 225 to 227 C. The acid prepared showed upon analysis: Calculated: C, 56.38, H, 5.36; found: C, 56.42, H, 5.41.

It will be apparent from the foregoing examples that a new series of compounds has been prepared which are particularly useful as intermediates in the preparation of certain pharmaceuticals related to barbituric acid and itsanalogues. Broadly speaking, th invention contemplates compounds and processes wherein the barbituric acid type ring nucleus is substituted in the 5 position by a B-nitroalkyl group. In its I broadest aspects the invention contemplates not only the derivatives of barbituric acid, but also .the derivatives of 2-thiobarbituric acid, malonyl- N-alkyl derivative salts in the manner indicated in the foregoing.

While several particular embodiments of this invention are shown above, it will be understood, of course, that the invention is not to be limited thereto, since many modifications may be made, and it is contemplated, therefore, by the ap pended claims, to cover any such modifications 'as fall within the true spirit and scope of this invention.

What is claimed is:

1. A compound selected from the class consisting of acids having the formula:

wherein R1 is selected from the group consisting of hydrogen and alkyl, wherein R2 is selected from the group consisting of hydrogen, alkyl and aryl, wherein R3 is selected from the group consisting of hydrogen, alkyl and aralkyl; and wherein X is selected from the group consisting of oxygen and sulfur; and the salts of said acids.

2. A barbituric acid derivative selected from the class consisting of compounds having the formula:

wherein R1 is selected from the group consisting of hydrogen and alkyl, wherein R2 is selected from the group consisting of hydrogen, alkyl and V aryl and wherein R3 is selected from the group consisting of hydrogen, alkyl, and aralkyl; and

the salts of said compounds.

4. A compound selected from the group consisting of the 5-(2-nitroalkyl) barbituric acids and their salts.

5. A compound selected from the group consisting of the 5-(2-nitroalkyl) Z-thiobarbituric acids and their salts.

6. 5-Benzyl 5 (2-nitro-n-butyl) -barbituric acid.

7. 5-Methyl 5 (2'-nitro-n-butyl) -2thiobarbituric acid.

8. 5-Ethyl-5-(2'-nitro n butyl) barbituric acid.

9. A process of preparing a compound having a barbituric acid type ring nucleus substituted in the 5 position with afi-nitroalkyl group which comprises reacting a nitroolefin in which the nitro group is attached to one of the doubly bound carbon atoms with a salt of a compound it) selected from the group consisting of barbituric acid and Z-thiobarbituric acid to produce the said compound having a barbituric acid ring type nucleus substituted in the five-position with a B-nitro alkyl group.

10. A process of preparing a 5-(2-nitroalkyl) barbituri-c acid derivative which comprises reacting a nitroolefin in which the nitro group is attached to one of the doubly bound carbon atoms with a salt of barbituric acid to produce a 5-(2' nitroalkyl) barbituric acid derivative.

11. The process recited in claim 10 wherein said salt is a quaternary ammonium salt of barbituric acid.

12. The process recited in claim 10 wherein said salt is a benzyltrimethylammonium salt of barbituric acid.

13. The process recited in claim 10 wherein said salt is an alkali metal salt.

1 1. The process recited in claim 10 wherein said salt is a potassium salt. 7

15. Aprocess of preparing a 5-(2'-nitroalkyl) Z-thiobarbituric acid derivative which comprises reacting a nitroolefin in which the nitro group is attached to one of the doubl bound carbon atoms with a salt of Z-thiobarbituric acid to produce a 5- (2-nitroalkyl) -2-thiobarbituric acid derivative.

16. The process recited in claim 15 wherein said salt is a quaternary ammonium salt of barbituric acid.

17. The process recited in claim 15 wherein said salt is a benzyltrimethylammoniumsalt of barbituric acid.

18. The process recited in claim 15 wherein said salt is an alkali metal salt.

19. The process recited in claim 15 wherein said salt is a potassium salt.

20. A process for the preparation of a 5-(2'- nitroalkyl)-5-alkyl derivative of a compound selected from the group consisting of barbituric acid and Z-thiobarbituric acid which comprises reacting a nitroolefin in which the nitro group is attached to one of the doubly bound carbon atoms with a quaternary ammonium salt of a 5-alkyl derivative of said compound to produce a 5-(2'- nitroalkyl) -5-alkyl'derivative of a compound selected from the group consisting of barbituric acid and Z-thiobarbituric acid.

21. The process recited in claim 20 wherein said salt is a benzyltrimethylammonium salt of said derivative.

22. A process of alkylating in the 5 position a compound selected from the group consisting of the salts of 5-(2-nitroalkyl) -barbituric acid and of 5-(2'-nitroalky1) -2-thiobarbituric acid which 1 comprises reacting said compound with an alkyl No references cited.

Certificate of Correction Patent No. 2,527,293 October 24, 1950 CARL T. BAHNER It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction as follows:

Column 1, line 9, for soporifices read sopom'fics; column 5, line 30, for fitering read filtering; column 6, line 60, for nitrol read m'tro;

and that the said Letters Patent. should be read as corrected above, so that the same may conform to the record of the case in the Patent Oflice. Signed and sealed this 2nd day of January, A. D. 1951.

THOMAS F. MURPHY,

Assistant Commissioner of Patents. 

1. A COMPOUND SELECTED FROM THE CLASS CONSISTING OF ACIDS HAVING THE FORMULA: 